A number of methods for treating joint diseases, such as loss of articular cartilage, rheumatoid arthritis, osteoarthritis or scapulo-humeral periarthritis, have been proposed for the recent 40 years. Although a method of articular cartilage regeneration by autologous cell transplantation is also attempted at present, this method requires several surgical operations, lacks simplicity and imposes great burden on patients. In cases where artificial joints are used, problems of bio-compatibility, durability, and the like arise. A method of treating joint diseases with a drug that dissolves these problems has been desired for long.
Under circumstances, a treating method in which hyaluronic acid is directly injected into the joint cavity is widely used in the field of medical treatment [e.g. Artz (product name) manufactured by Seikagaku Corporation and sold by Kaken Pharmaceutical is used]. Hyaluronic acid is one of the main components of synovial fluid and produces analgesic effect in joints due to its viscoelastic effect and anti-inflammatory effect. Generally, in the synovial fluid of patients with arthritis such as osteoarthritis, rheumatoid arthritis, etc., it is known that the concentration and molecular weight of hyaluronic acid are lower than the concentration and molecular weight in normal synovial fluid. This is considered to be associated with the occurrence of painful conditions attributable to the decreasing of the lubricant effect and shock-absorbing effect of the synovial fluid. However, the clearance of hyaluronic acid in the joint cavity is quick. Although use of high molecular weight (about 1,900,000 daltons) hyaluronic acid [Suvenyl (product name) manufactured by Aventis Pharma Japan and sold by Chugai Pharmaceutical] has been tried to prolong the residence time, low temperature flow is necessary because of its high molecular weight and injection pressure tends to be high because of its high viscosity. The residence time of this hyaluronic acid in the joint cavity is about five days (Japanese Pharmacology and Therapeutics, 22 (S-3), S779 (1994)), and the duration of analgesic effect is about one week. Further sustaining of the effect is also demanded for the purpose of improving compliance in patients.
On the other hand, another trial to prolong the residence time has been made by partially cross-linking hyaluronic acid chemically [for example, Synvisk (product name) from Genzyme Biosurgery (Japanese Unexamined Patent Publication No. 4-261664 (U.S. Pat. No. 5,399,351; EP Patent No. 466300)); and Restylane (product name) from Q-Med (Dermatologic Surgery, 24, 1317-1325, 1998)]. However, problems such as induction of inflammation by the cross-linking agent are apprehended. A gel material utilizing physical cross-linking by hydrogen bonds or the like between hyaluronic acid molecules has also been reported (International Patent Publication Number WO00/27405). However, the bridge begins to collapse when the gel material is dissolved in water. Therefore, it is difficult to distribute this material as an easy-to-handle liquid preparation (i.e. injection) like the currently used hyaluronic acid preparations.
On the other hand, poly-N-substituted acrylamide derivatives, poly-N-substituted methacrylamide derivatives, polyvinyl methyl ethers, polyvinyl alcohol partial oxide, etc. are known as thermo-responsive polymers. As a thermo-responsive polymer highly safe in the living body, a polyethylene oxide-polypropylene oxide-polyethylene oxide block polymer (PEO-PPO-PEO; product name: Pluronic) is known, and was approved by the US Food and Drug Administration (FDA) (approval grades: F68 and F127). As a similar polymer, a polypropylene oxide-polyethylene oxide-polypropylene oxide block polymer (PPO-PEO-PPO; product name: Pluronic R) is known. It is reported that, when these polymers are used alone, it is possible to increase their viscosity and to turn them into gel by increasing the temperature (Adv. Drug. Delivery Rev., 31, 197-221 (1998)). However, in order to achieve such increased viscosity or gelation, it is necessary to use them at a high concentration of 16% w/v or more, which is disadvantageous in terms of safety and drug carrying ratio.
A polyethylene oxide-polylactic acid/polyglycolic acid copolymer-polyethylene oxide block polymer (PEO-PLGA-PEO; product name: Regel) or a polylactic acid/polyglycolic acid copolymer-polyethylene oxide-polylactic acid/polyglycolic acid copolymer block polymer (PLGA-PEO-PLGA; product name: Regel) each of which has a polylactic acid/polyglycolic acid copolymer instead of PPO in its hydrophobic portion; or a polyethylene oxide-polylactic acid-polyethylene oxide block polymer (PEO-PLA-PEO) or a polylactic acid-polyethylene oxide-polylactic acid block polymer (PLA-PEO-PLA) each of which has a polylactic acid polymer instead of PPO in its hydrophobic portion is known to have a thermo-responsive function similar to the thermal responsiveness as described above (International Patent Publication Number WO99/18142).
Although common thermo-reversible hydrogel materials composed of such a thermo-responsive polymer and a hydrophilic polymer have been reported (Japanese Unexamined Patent Publications No. 5-262882, No. 9-227329, No. 11-169703; International Patent Publication Number WO95/15152), no example in which hyaluronic acid is combined with PEO-PPO-PEO, PPO-PEO-PPO, PEO-PLGA-PEO, PLGA-PEO-PLGA, PEO-PLA-PEO or PLA-PEO-PLA has been reported to date. Besides, such hydrogel materials are for use in external preparations or perfumes/cosmetics, and are not intended to be injected into the living body (e.g. into the joint cavity). A thermo-responsive polymer in which PEO-PPO-PEO is grafted on polyacrylic acid (International Patent Publication Number WO97/24430 (U.S. Pat. No. 5,709,815)) and a polymer in which poly-N-isopropyl acrylamide is grafted on hyaluronic acid (Biomacromol., 2, 856-863 (2001)) have also been reported. However, polyacrylic acid and poly-N-isopropyl acrylamide have safety problems such as the remaining of mutagenic monomers. Although a material in which hyaluronic acid is bound to Pluronic (Journal of Controlled Release, Vol. 80, Issue 1-3, pp. 69-77 (Apr. 23, 2002)) has also been reported, pharmaceutical use of the material itself is neither disclosed nor suggested. Besides, since the molecular weight of the material described in this document is 12,600, it is hard to be discharged from the living body and thus is not suitable for pharmaceutical use.
As described above, at present, there is no safe hyaluronic acid base material which is appropriate for use in practical hyaluronic acid preparations that are capable of distribution at room temperature, have a low viscosity allowing easy injection, and yet reside in the joint cavity for a long period of time to show analgesic effect.
Although use of hyaluronic acid preparations as an assisting agent for ophthalmic surgery (product name: Healon) or as a tissue repairing agent is also known, no assisting agent or treating agent for surgical operation has been known yet which is capable of distribution at room temperature, has a low viscosity allowing easy injection, and has an appropriate viscosity during operation.